It is well documented that excess body fat suppresses the hypothalamic-pituitary-gonadal (HPG) axis, which reduces endogenous testosterone production.1-3 One mechanism contributing to the HPG-axis suppression is elevated circulating estradiol, caused by aromatization of testosterone in adipocytes.2,3 In addition, insulin resistance - a hallmark of obesity 4 - is associated with a decreased Leydig cell testosterone secretion.5 Obesity in men is associated with a drop in testosterone levels comparable to that of 10 years of aging.

Here we present the results of a study that investigated the effect of treatment with testosterone undecanoate injections on glycemic control, beta cell function, and body composition.6

Key Points

Treatment with testosterone undecanoate injections for up to 29 months (mean 15 months) resulted in a significant improvement in HbA1C (9 mmol/mol, P = 0.03) and a 52% improvement in beta cell function, as demonstrated by increased insulin secretion (evaluated by HOMA%B).

There was a significant 3.5 kg reduction in fat mass and 2.9 kg increase in lean body mass, and a trend for increased basal metabolic rate (BMR).

The insulinotropic effect of testosterone reported in the present study is especially interesting when considering that there is a progressive deterioration in beta-cell function in type 2 diabetes, and that early treatment can reverse beta-cell function impairment.

What is known about obesity-related secondary hypogonadism

The prevalence of testosterone deficiency in obese men can be as high as 79%.7,8 With the demographic trends of increased longevity and rising prevalence of obesity and type 2 diabetes, it is likely that obesity-related testosterone deficiency will become even more prevalent. Clinical features of obesity-related testosterone deficiency include sexual dysfunction (erectile dysfunction and poor libido), osteopenia and osteoporosis, reduced feelings of well-being, fatigue, impaired mood and concentration, sarcopenia, increased fat mass and dyslipidaemia.3 It is alarming that this adverse health condition is underrecognized and underdiagnosed.3

A growing body of evidence shows that testosterone therapy improves insulin sensitivity.9 A notable randomized placebo-controlled trial showed that testosterone therapy improves insulin sensitivity in men with type 2 diabetes, as measured by an improved glucose disposal rate during hyperinsulinemic euglycemic clamp (the gold standard method for evaluating insulin sensitivity).10 Increased insulin sensitivity has also been shown using the 2-stage glucose clamp method.11 Other controlled trials show that testosterone therapy reduces insulin resistance (as shown by reduced HOMA IR) and improves glycemic control (lowering of HbA1C and fasting glucose) in hypogonadal men with type 2 diabetes.12,13

These observations have been corroborated in animal studies that have shown beneficial effects of testosterone treatment on components of glucose uptake.14 In vitro data on the effects of testosterone in human subcutaneous adipocytes show increased expression of Glucose transporter type 4 (GLUT4) and Protein Kinase B (Akt), which in turn would be expected to increase glucose uptake and insulin sensitivity.10

However, the effects of testosterone on beta cell insulin release in hypogonadal men has not yet received much scientific investigation. In the TIMES 2 study, there were no changes in HOMA %B after testosterone therapy for 12 months.13 In normoglycaemic men ages 18-54 (mean 28) years old, endogenous testosterone levels correlated negatively with β-cell secretion (C-peptide).15

What this study adds

The primary outcome of this study was change in HbA1C in obese hypogonadal men following testosterone undecanoate intramuscular therapy. Secondary outcomes were changes in measures of insulin sensitivity and beta cell functioning (HOMA2 IR and HOMA %B, respectively), metabolic profile, body fat and lean mass, and fasting lipid profile.

13 obese hypogonadal men, 7 of whom had type 2 diabetes, were treated with testosterone undecanoate injection for 6 to 29 months. The dosing schedule of the testosterone undecanoate treatment was, as per prescribing information, as follows; after an initial intramuscular injection of 1000 mg testosterone undecanoate, the second injection was administered 6 weeks later, and all subsequent injections at intervals of 12 weeks.

As expected, there was a significant improvement in serum trough testosterone levels (the lowest level right before the next injection) between baseline and follow-up assessments (mean serum trough testosterone; from 6.7 nmol/L to 15.2 nmol/L.

Significant improvements in body composition were documented, with a reduction in fat mass of 3.5 kg and an increase in lean body mass of 2.9 kg, see figure 1. Body fat percentage was reduced by 2.8%.

HbA1C significantly improved from 7.3 to 6.5% (56 to 47 mmol/mol). Although there was a trend for reduction in insulin resistance (HOMA IR dropped from 5.5 to 4.5) this did not reach statistical significance. There was however, a significant improvement in beta-cell function (mean HOMA %B improved by 52%), despite only non-significant reductions in fasting glucose and insulin levels.

Although there was a numerical increase in basal metabolic rate (BMR), this also failed to reach significance. There were no changes in lipid parameters. There was a small increase in PSA from (0.8 to 1.1 ng/mL), which remained well within the normal range in all subjects.

By convention, a normal-weight, healthy person younger than 35 years old would have a HOMA-B (surrogate marker of beta-cell function) of 100% and a HOMA-IR (insulin resistance) of 1.0. These calibrations reflect the balance between endogenous glucose production and beta-cell insulin secretion, but only during the basal state.

Commentary

This is the first study showing that testosterone treatment improved beta cell function (measured by HOMA %B).6 It is likely that the improvement in beta cell function is mediated, at least in part, through direct effects of testosterone on beta-cell insulin release.18,19 Experimental research shows that testosterone is important for insulin secretion in males.20 Testosterone seems to increase glucose-stimulated insulin secretion in a manner similar to glucagon like peptide-1 (GLP-1).19 Androgen receptor-deficient pancreatic islets exhibit altered expression of genes involved in inflammation and insulin secretion, demonstrating the importance of androgen action in β-cell health in the male, with implications for development of type 2 diabetes in men.21

The body composition improvements seen in this study - reduction in fat mass and increase in lean body mass – are some of the most well documented effects of testosterone treatment. A growing number of studies are also showing improvements in HbA1C,12,22-24 which was confirmed in this study.

An important limitation of this study is the small number of subjects. This limits the statistical power to detect effects that are caused by testosterone treatment, and likely explains the lack of change in lipid profiles that has been found in several other studies of testosterone therapy in obese men. Likewise, this also explains why the reduction in insulin resistance did not reach statistical significance (meaning that it could have been caused by chance).

Furthermore, given the well-established association between BMR and lean body mass [28], it is possible that significant changes in BMR would have been detected in a larger number of subjects. Another limitation is the relatively short duration of testosterone undecanoate therapy.

Nevertheless, the insulinotropic effect of testosterone reported in the present study is especially interesting when considering that there is a progressive deterioration in beta-cell function in type 2 diabetes.25 Pancreatic islet function is about 50% of normal at the time of type 2 diabetes diagnosis.25 Impaired beta-cell function (and possibly beta-cell mass) appears to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility has probably not been passed.25 Improved beta-cell function is likely a mechanism contributing to remission of type 2 diabetes that has been reported with long-term testosterone undecanoate treatment.26 This highlights the importance of starting testosterone treatment as early as possible in hypogonadal men, when the “window of reversibility” of impaired beta-cell function is still open.